Transdermal administration can, in certain cases, be a favourable administration route for medicaments; in fact, such a route makes it possible to optimize the systemic effect or topical effect, to increase the therapeutic effectiveness, to reduce undesirable effects and to avoid, in the case of a systemic action, the effect of a first passage through the liver.
Transdermal systems are generally forms intended to make possible the passage of active principles, incorporated in a reservoir, through the skin, either in order to have a systemic action or in order to obtain a more local action, by fixation in the underlying tissues of the skin.
Such systems can take essentially two forms:
a bag which acts as reservoir, limited on one of its surfaces by an adhesive semi-permeable membrane placed against the skin and which controls the release and the passage of the active principle towards the skin; in this case, the membrane controls the release of the active principles and therefore, in the case of a systemic action, their blood concentration. PA1 a polymeric matrix which acts as reservoir and is associated with an adhesive, which controls the release towards the skin of the active principle; this form contains two variants: (1) either the polymeric matrix consists of an adhesive, with responsibility for attaching the system to the skin, which acts as reservoir, (2) or the polymeric matrix and the adhesive are separate and only the polymeric matrix acts as reservoir and controls the release of the active principle, the only function of the adhesive being to hold the system onto the skin without hindering the passage of the active principle. PA1 a reservoir containing nicotine and comprising from 60 to 95 weight % of an EVA copolymer having a vinyl acetate content of approximately 40%, PA1 an adhesive layer comprising nicotine dissolved in a polymer consisting essentially of a mixture of high molecular weight PIB and of low molecular weight PIB, PA1 and an agent for controlling the release of the active principle, arranged between the reservoir and the adhesive. PA1 the adhesive acts as reservoir, which only makes possible actions of short duration, excessively large active principle charges leading to a loss in adhesive power (limited capacity for charging with active principle); PA1 each of the systems is only suitable for a specific active principle; PA1 the rate of release of the active principle is related to the nature of the adhesive.
The rate of release is thus controlled either by the membrane placed between the reservoir and the skin or by the reservoir itself (generally then known as matrix).
Taking into account the above, many factors must be considered in developing a transdermal system.
It is, in particular, important to have available a reservoir which makes possible a steady release of the active principle, providing a constant blood concentration or a sufficient concentration in the underlying tissues, for a sufficiently long period of time (several days), so as to avoid excessively frequent applications of such systems.
Many systems have been proposed in the prior art and recommend particularly the presence of a membrane which controls the release of the active principles and thus, in particular, their blood concentration.
In the case where the skin is not sufficiently permeable to the active principle, permeability stimulators are combined with said active principles.
Application EP 399 765, on behalf of Advanced Polymer Systems Inc., describes particularly a transdermal system including an impermeable support and a matrix, made of appropriate adhesive material such as a polyisobutylene or an acrylic, and which includes a plurality of polymeric particles; these polymeric particles include at least one penetration stimulator (or permeability stimulator), whereas the active principle to be administered can be present either in the solid form or in the liquid form in the said matrix or in the said polymeric particles.
It is specified that the choice of the matrix and of the permeability stimulator are related to the active principle; in particular, when the active principle is levonorgestrel, the matrix, which must be both a reservoir for active principles and for polymeric particles, is EVA and the stimulator is an ethyl acetate/ethanol mixture and is included in the said polymeric particles, which can be prepared from unsaturated monoethylenic monomers (acrylic or methacrylic acid esters).
International Application WO 90/07940, on behalf of Noven Pharmaceuticals Inc., describes a transdermal system which comprises an adhesive layer which includes the active principle and an impermeable support.
The adhesive layer is multipolymeric and advantageously comprises the active principle, a multipolymer containing EVA and including an acrylic polymer (adhesive), an elastomeric polymer (gum) and a tackifying agent.
The EVA copolymers (vinyl acetate: between 4 and 80 weight % and ethylene: 15 to 90%) can be either copolymers or acrylic acid/ethylene/vinyl acetate terpolymers.
The EVA/acrylate ratio is preferably between 20:1 and 1:20 by weight. A crosslinking agent can optionally be used. The composition advantageously comprises between 3 and 20% of EVA, between 25 and 70% of acrylate and between 2 and 20% of gum.
International Application WO 91/16085, on behalf of Alza Corporation, describes adhesives based on polyisobutylene (PIB) for transdermal systems.
It describes in particular a transdermal system comprising:
European Patent 318,385, on behalf of Pierre Fabre Medicament, describes and claims a multilamellar device for the transdermal administration of trinitrin composed successively of a support made of a flexible and occlusive material (EVA/PVDC/EVA-type co-extruded thermoplastic film), an active adhesive reservoir based on polymers of acrylic or silicone type incorporating the active principle, a membrane for transfer of the active principle of polyurethane type, a hypoallergenic adhesive interface self-fed by the reservoir with active principle, and a protector made from a rigid or semi-rigid film coated with an anti-adhesive (ordinary paper, aluminized paper, polyesters or PVC), characterized in that it is constructed from a first module comprising the support, the active adhesive reservoir and a temporary protective paper and from a second module composed of the transfer membrane, the adhesive interface and the anti-adherent protector, the two modules being bonded to each other, after removal of the protective paper from the first module, by pressing the active reservoir against the permeable membrane for transfer of the active principle.
European Patent Application 328,806, on behalf of Paco Pharmaceutical Services, describes a transdermal system for estradiol which comprises an impermeable; support and a matrix comprising from 60 to 95% of an adhesive polymer (vinyl acetate/acrylate multipolymer), from 5 to 20% of a solvent (propylene glycol and derivatives), from 0.2 to 4% of a skin penetration stimulator (polyoxyethylene ester, polyethyleneglycolsorbitan mono-9-octadecenoic acid ester) and from 0.5% of an active principle (oestrogen and derivatives).
These documents, taken as a whole, show the variety of the transdermal devices containing particularly a polymeric matrix based on EVA; however, these devices of the prior art have a certain number of disadvantages:
These disadvantages particularly make it difficult, with these transdermal systems, to obtain controlled blood levels of active principles, below the limiting flows due to the skin, lasting several days.